Background <p>Increasing evidence suggests a link between major depressive disorder (MDD) and inflammatory pathways. Sertraline, a commonly used selective serotonin reuptake inhibitor (SSRI), may influence inflammatory cytokine levels. This systematic review and meta-analysis aimed to elucidate the association between the antidepressant sertraline and inflammatory processes and to delineate the roles of key cytokines within this context.</p> Methods <p>Electronic searches of the Web of Science, MEDLINE, and Embase databases (from inception to August 8, 2025) yielded 890 unique records. The included studies measured serum concentrations of inflammatory cytokines in patients with major depressive disorder (MDD) before and after sertraline treatment, with subsequent analysis of the effects of sertraline on these biomarkers. Two independent investigators performed the literature screening and data extraction. Pooled effect estimates were calculated using random effects meta-analysis models.</p> Results <p>Eleven studies (406 participants) were included. The results demonstrated significant increases in both IL-6 levels (SMD = 0.87; 95% CI: 0.16 to 1.58; Z = 2.41; <i>p</i> = 0.02) and TNF-α levels (SMD = 0.76; 95% CI: 0.14 to 1.71; Z = 2.30; <i>p</i> = 0.02) following sertraline treatment.</p> Conclusion <p>Sertraline significantly modulates IL-6/TNF-α levels, suggesting that this pathway may partly mediate its antidepressant effects.</p>